Transforming growth factor-beta (TGF-β) is a prototype for a large family of growth and differentiation factors that regulate development. TGF-β family members activate transmembrane serine/threonine receptor kinases, thereby initiating a signaling cascade via Smads, a novel class of intracellular signaling effectors that regulate gene expression. TGF-β is a potent inducer of growth arrest in many cell types, including epithelial cells. This activity is the basis of the tumor suppressor role of the TGF-β signaling system in carcinomas. Other activities, including TGF-β-induced epithelial-to-mesenchymal differentiation, contribute to cancer progression.
TGF-β family signaling is of special relevance in mesenchymal differentiation, including bone development. Deregulated expression or activation of components of this signaling system can contribute to skeletal diseases, e.g. osteoarthritis. See Wakefield, et al. (2002) Current Opinion in Genetics & Development 12:22-29; Siegel, et al. (2003) Nature Reviews (Cancer) 3:807-820; Dumont, et al. (2003) Cancer Cell 3:531-536.
PCT patent application WO 02/0948332 describes a genus of dihydropyrrolopyrazole compounds useful for treating disorders associated with enhanced TGF-β signaling activity or overproduction. PCT patent application WO 04/04382 describes an anhydrous form of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole.
It has been surprisingly discovered that 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin -4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole can be prepared in a crystalline monohydrate form having the advantageous properties relative to the anhydrous form of superior solid handling properties on a large scale, ease of purification by crystallization, and thermodynamic stability under conditions of pharmaceutical processing and storage. A manufacturing process for the new form has also been discovered.